Vitamin B6

High levels of circulating homocysteine are associated with an increased risk of cardiovascular disease. Randomized controlled trials have demonstrated that supplementation with B vitamins, including vitamin B6, could effectively reduce homocysteine levels. However, homocysteine lowering by B vitamins has failed to lower the risk of adverse cardiovascular outcomes in high-risk individuals. (More information)

Although supplementation with vitamin B6 and other B vitamins has not been associated with improved cognitive performance or delayed cognitive deterioration in the elderly, recent studies suggest that vitamin B6 might help reduce the risk of late-life depression. (More information)

Pharmacologic doses of vitamin B6 are used to treat seizures in rare inborn errors of vitamin B6 metabolism. Also, randomized controlled trials support the use of vitamin B6 to treat morning sickness in pregnant women and suggest a possible benefit in the management of premenstrual syndrome and carpal tunnel syndrome. (More information)

Vitamin B6 is found in a variety of foods, including fish, poultry, nuts, legumes, potatoes, and bananas. (More information)

Vitamin B6 is a water-soluble vitamin that was first isolated in the 1930s. The term vitamin B6 refers to six common forms, namely pyridoxal, pyridoxine (pyridoxol), pyridoxamine, and their phosphorylated forms. The phosphate ester derivative pyridoxal 5'-phosphate (PLP) is the bioactive coenzyme form involved in over 4% of all enzymatic reactions (see figure) (1-3).

Function

Vitamin B6 must be obtained from the diet because humans cannot synthesize it. PLP plays a vital role in the function of over 100 enzymes that catalyze essential chemical reactions in the human body (4). PLP-dependent enzymes have been classified into five structural classes known as Fold Type I-V (5):

Fold Type I - aspartate aminotransferase family

Fold Type II - tryptophan synthase family

Fold Type III - alanine racemase family

Fold Type IV - D-amino acid aminotransferase family

Fold Type V - glycogen phosphorylase family

The many biochemical reactions catalyzed by PLP-dependent enzymes are involved in essential biological processes, such as hemoglobin and amino acid biosynthesis, as well as fatty acidmetabolism. Of note, PLP also functions as a coenzyme for glycogen phosphorylase, an enzyme that catalyzes the release of glucose from stored glycogen. Much of the PLP in the human body is found in muscle bound to glycogen phosphorylase. PLP is also a coenzyme for reactions that generate glucose from amino acids, a process known as gluconeogenesis(6).

Nervous system function

In the brain, the PLP-dependent enzyme aromatic L-amino acid decarboxylase catalyzes the synthesis of two major neurotransmitters: serotonin from the amino acid tryptophan and dopamine from L-3,4-dihydroxyphenylalanine (L-Dopa). Other neurotransmitters, including glycine, D-serine, glutamate, histamine, and gamma-aminobutyric acid (GABA), are also synthesized in reactions catalyzed by PLP-dependent enzymes (7).

Hemoglobin synthesis and function

PLP functions as a coenzyme of 5-aminolevulinic acid synthase, which is involved in the synthesis of heme, an iron-containing component of hemoglobin. Hemoglobin is found in red blood cells and is critical to their ability to transport oxygen throughout the body. Both pyridoxal and PLP are able to bind to the hemoglobin molecule and affect its ability to pick up and release oxygen. However, the impact of this on normal oxygen delivery to tissues is not known (6, 8). Vitamin B6 deficiency may impair hemoglobin synthesis and lead to microcytic anemia(3).

Tryptophan metabolism

Deficiency in another B vitamin, niacin, is easily prevented by adequate dietary intakes. The dietary requirement for niacin and the niacin coenzyme, nicotinamide adenine dinucleotide (NAD), can be also met, though to a fairly limited extent, by the catabolism of the essential amino acid tryptophan in the tryptophan-kynurenine pathway (see figure). Key reactions in this pathway are PLP-dependent; in particular, PLP is the cofactor for the enzyme kynureninase, which catalyzes the conversion of 3-hydroxykynurenine to 3-hydroxyanthranilic acid. A reduction in PLP availability appears to primarily affect kynureninase activity, limiting NAD production and leading to higher concentrations of kynurenine, 3-hydroxykynurenine, and xanthurenic acid in blood and urine (see figure) (9). Thus, while dietary vitamin B6 restriction impairs NAD synthesis from tryptophan, adequate PLP levels help maintain NAD formation from tryptophan (10). The effect of vitamin B6 inadequacy on immune activation and inflammation may be partly related to the role of PLP in the tryptophan-kynurenine metabolism (see Disease Prevention).

Hormone function

Steroidhormones, such as estrogen and testosterone, exert their effects in the body by binding to steroid hormone receptors in the nucleus of target cells. The nuclear receptors themselves bind to specific regulatory sequences in DNA and alter the transcription of target genes. Experimental studies have uncovered a mechanism by which PLP may affect the activity of steroid receptors and decrease their effects on gene expression. It was found that PLP could interact with RIP140/NRIP1, a repressor of nuclear receptors known for its role in reproductive biology (11). Yet, additional research is needed to confirm that this interaction can enhance RIP140/NRIP1 repressive activity on steroid receptor-mediated gene expression. If the activity of steroid receptors for estrogen, progesterone, testosterone, or other steroid hormones can be inhibited by PLP, it is possible that vitamin B6 status may influence one's risk of developing diseases driven by steroid hormones, such as breast and prostatecancers(6).

Nucleic acid synthesis

The synthesis of nucleic acids from precursors thymidine and purines is dependent on folatecoenzymes. The de novo thymidylate (dTMP) biosynthesis pathway involves three enzymes: dihydrofolate reductase (DHFR), serine hydroxymethyltransferase (SHMT), and thymidylate synthase (TYMS) (see figure). PLP serves as a coenzyme for SHMT, which catalyzes the simultaneous conversions of serine to glycine and tetrahydrofolate (THF) to 5,10-methylene THF. The latter molecule is the one-carbon donor for the generation of dTMP from dUMP by TYMS.

Deficiency

Severe deficiency of vitamin B6 is uncommon. Alcoholics are thought to be most at risk of vitamin B6 deficiency due to low dietary intakes and impaired metabolism of the vitamin. In the early 1950s, seizures were observed in infants as a result of severe vitamin B6 deficiency caused by an error in the manufacture of infant formula (7). Abnormal electroencephalogram (EEG) patterns have also been reported in vitamin B6-deficient adults. Other neurologic symptoms observed in severe vitamin B6 deficiency include irritability, depression, and confusion; additional symptoms include inflammation of the tongue, sores or ulcers of the mouth, and ulcers of the skin at the corners of the mouth (12).

The Recommended Dietary Allowance (RDA)

Since vitamin B6 is involved in many aspects of metabolism, especially in amino acid metabolic pathways, an individual's protein intake is likely to influence the requirement for vitamin B6(13). Unlike previous recommendations issued by the Food and Nutrition Board (FNB) of the Institute of Medicine, the most recent RDA for vitamin B6 was not expressed in terms of protein intake, although the relationship was considered in setting the RDA (14). The current RDA was revised by the Food and Nutrition Board (FNB) in 1998 and is presented in the table below.

Several enzymatic reactions in the tryptophan-kynurenine pathway are dependent on vitamin B6coenzyme, pyridoxal 5'-phosphate (PLP) (see figure) (see Tryptophan metabolism above). This pathway is known to be activated during pro-inflammatory immune responses and plays a critical role in immune tolerance of the fetus during pregnancy (15). Key intermediates in the tryptophan-kynurenine pathway are involved in the regulation of immune responses. Several tryptophan derivatives have been found to induce the death (apoptosis) or block the proliferation of certain types of immune cells, such as lymphocytes (in particular T-helper 1). They can also inhibit the production of pro-inflammatory cytokines (reviewed in 15). There is evidence to suggest that adequate vitamin B6 intake is important for optimal immune system function, especially in older individuals (16, 17). Yet, chronic inflammation that triggers tryptophan degradation and underlies many diseases (e.g., cardiovascular diseases and cancers) may precipitate the loss of PLP and increase vitamin B6 requirements. Additional research is needed to evaluate whether vitamin B6 intakes higher than the current RDA could prevent and/or reverse immune system impairments (see also Vitamin B6 and inflammation below).

Cardiovascular diseases

The use of multivitamin supplements (including vitamin B6) has been associated with a 24% lower risk of incidental coronary artery disease (CAD) in a large prospective study of 80,082 women from the US Nurses' Health Study cohort (18). Using food frequency questionnaires, the authors observed that women in the highest quintile of vitamin B6 intakes from both food and supplements (median, 4.6 mg/day) had a 34% lower risk of CAD compared to those in the lowest quintile (median, 1.1 mg/day). CAD is characterized by the abnormal stenosis (narrowing) of coronary arteries (generally due to atherosclerosis), which can result in a potentially fatal myocardial infarction (heart attack). More recently, a prospective study that followed a Japanese cohort of over 40,000 middle-aged individuals for 11.5 years reported a 48% lower risk of myocardial infarction in those in the highest (mean, 1.6 mg/day) versus lowest quintile (mean, 1.3 mg/day) of vitamin B6 intakes in non-supplement users (19).

Early observational studies have also demonstrated an association between suboptimal pyridoxal 5'-phosphate (PLP) plasma level, elevated homocysteine blood level, and increased risk of cardiovascular diseases(20-22). More recent research has confirmed that low plasma PLP status is a risk factor for CAD. In a case-control study, which included 184 participants with CAD and 516 healthy controls, low plasma PLP levels (<30 nanomoles/liter) were associated with a near doubling of CAD risk when compared to higher PLP levels (≥30 nanomoles/liter) (23). In a nested case-control study based on the Nurses' Health Study cohort and including 144 cases of myocardial infarction (of which 21 were fatal), women in the highest quartile of blood PLP levels (≥70 nanomoles/liter) had a 79% lower risk of myocardial infarction compared to those in the lowest quartile (<27.9 nanomoles/liter) (24).

Vitamin B6 and homocysteine

Even moderately elevated levels of homocysteine in the blood have been associated with increased risk for cardiovascular disease (CVD), including cardiac insufficiency (heart failure), CAD, myocardial infarction, and cerebrovascular attack (stroke) (25). During protein digestion, amino acids, including methionine, are released. Methionine is an essential amino acid and precursor of S-adenosylmethionine (SAM), the universal methyl donor for most methylation reactions, including the methylation of DNA, RNA, proteins, and phospholipids (see figure). Homocysteine is an intermediate in the metabolism of methionine. Healthy individuals utilize two different pathways to regenerate methionine from homocysteine in the methionine remethylation cycle (see figure). One pathway relies on the vitamin B12-dependent methionine synthase and the methyl donor, 5-methyl tetrahydrofolate (a folate derivative), to convert homocysteine back to methionine. The other reaction is catalyzed by betaine homocysteine methyltransferase, which uses betaine as a source of methyl groups for the formation of methionine from homocysteine. Moreover, two PLP-dependent enzymes are required to convert homocysteine to the amino acid cysteine in homocysteine transsulfuration pathway: cystathionine beta synthase and cystathionine gamma lyase (see figure). Thus, the amount of homocysteine in the blood may be influenced by nutritional status of at least three B vitamins, namely folate, vitamin B12, and vitamin B6.

Deficiencies in one or all of these B vitamins may affect both remethylation and transsulfuration processes and result in abnormally elevated homocysteine levels. An early study found that vitamin B6 supplementation could lower blood homocysteine levels after an oral dose of methionine was given (i.e., a methionine load test) (26), but vitamin B6 supplementation might not be effective in decreasing fasting levels of homocysteine. In a recent study conducted in nine healthy young volunteers, the rise of homocysteine during the postprandial period (after a meal) was found to be greater with marginal vitamin B6 deficiency (mean plasma PLP level of 19 nanomoles/liter) as compared to vitamin B6 sufficiency (mean PLP level of 49 nanomoles/liter) (27). The authors reported an increased rate of cystathionine synthesis with vitamin B6 restriction, suggesting that homocysteine catabolism in the transsulfuration may be maintained or enhanced in response to a marginal reduction in PLP availability. Yet, the flux ratio between methionine cycle and transsulfuration pathway appeared to favor homocysteine clearance by remethylation rather than transsulfuration in six out of nine participants (27).

Numerous randomized controlled trials, many in subjects with existing hyperhomocysteinemia and vascular dysfunction, have demonstrated that supplementation with folic acid, alone or combined with vitamin B6 and vitamin B12, could effectively reduce fasting plasma homocysteine concentrations. In 19 intervention studies recently included in a meta-analysis, reductions in homocysteine level in the blood following B-vitamin supplementation ranged between 7.6% and 51.7% compared to baseline levels (28). In contrast, studies supplementing individuals with only vitamin B6 have usually failed to show an effect on fasting levels of homocysteine (29, 30). Of the three supplemental B vitamins, folic acid appears to be the main determinant in the regulation of fasting homocysteine levels when there is no coexisting deficiency of vitamin B12 or vitamin B6(31). Yet, the effect of homocysteine lowering on CVD risk reduction is debated. A recent meta-analysis of nine randomized controlled trials reported a 10% reduction in stroke events with supplemental B vitamins, with greater benefits for high-risk subjects (e.g., those with kidney disease) (32). However, most systematic reviews and meta-analyses of B-vitamin intervention studies to date have indicated a lack of causality between the decrease of fasting homocysteine levels and the prevention of cardiovascular events (28, 33-35). Moreover, B-vitamin supplementation trials in high-risk subjects have not resulted in significant changes in carotid intima-media thickness (CIMT) and flow-mediated dilation (FMD) of the brachial artery, two markers of vascular health used to assess atherosclerotic progression (36). Finally, in the Western Norway B Vitamin Intervention Trial (WENBIT), a randomized, double-blind, placebo-controlled trial in 87 subjects with suspected CAD, vitamin B6 supplementation (40 mg/day of pyridoxine) for a median of 10 months had no effect on coronary stenosis progression, assessed by quantitative angiography(37).

It has been suggested that antiplatelet therapy used in the primary prevention of CVD might interfere with the effect of homocysteine lowering by B vitamins on CVD risk (38). In this context, a post-hoc subgroup analysis of the multicenter, randomized, double blind, placebo-controlled VITATOPS trial (39) proposed that the small benefit of homocysteine-lowering by B vitamins might be cancelled in patients treated with antiplatelet drugs (40). Yet, the benefit of B-vitamin supplementation in primary prevention (i.e., in non-antiplatelet users) remains to be established.

Vitamin B6 and inflammation

A growing body of evidence currently suggests that low vitamin B6 status may increase the risk of cardiovascular disease through mechanisms independent of homocysteine lowering (41-43). Markers of immune activation and inflammation have been associated with hyperhomocysteinemia (homocysteine levels >15 micromoles/liter) in individuals with coronary artery disease (CAD) (44). In fact, inflammation is involved in the early steps of atherosclerosis in which lipids deposit in plaques (known as atheromas) within arterial walls and increase the risk of CAD (45). In a case-control study that included 267 patients with CAD and 475 healthy controls, plasma PLP concentrations were inversely correlated with the levels of two markers of systemic inflammation, C-reactive protein (CRP) and fibrinogen (46). Yet, the study suggested that suboptimal PLP levels (<36.3 nanomoles/liter) might contribute to an increased risk of CAD independently of inflammation since the risk was unchanged after adjustment for inflammation markers (unadjusted odds ratio (OR): 1.71 vs. multivariate adjusted OR: 1.73). Furthermore, the analysis of inflammation markers in 2,686 participants of the US National Health and Nutrition Examination Survey (NHANES) 2003-2004 indicated that serum CRP concentrations were inversely related to total vitamin B6 intakes (from both food and supplements). Specifically, the risk of having serum CRP levels greater than 10 mg/L (corresponding to high inflammatory activity) was 57% higher in individuals with vitamin B6 intakes lower than 2 mg/day compared to those with intakes equal to and above 5 mg/day (41). In addition, the prevalence of inadequate vitamin B6 status (plasma PLP levels <20 nanomoles/liter) with intakes lower than 5 mg/day was systematically greater in individuals with high vs. low serum CRP concentrations (>10 mg/L vs. ≤3 mg/L), suggesting that inflammation might impair vitamin B6metabolism. These observations were confirmed in the study of another cohort (Framingham Offspring Study) in which vitamin B6 status was linked to an overall inflammatory score based on the levels of 13 inflammation markers (including CRP, fibrinogen, tumor necrosis factor-alpha, and interleukin-6) (42). Specifically, plasma PLP levels were 24% lower in individuals in the highest vs. lowest tertile of inflammatory score. Moreover, the inverse correlation between PLP levels and inflammatory scores remained significant regardless of vitamin B6 intakes, questioning again the nature of this relationship. Interestingly, a recent analysis of data collected in the WENBIT study demonstrated that systemic inflammation was associated with an increased degradation of pyridoxal (PL) to 4-pyridoxic acid (PA), supporting the use of the ratio PA:(PL+PLP) as a marker of both vitamin B6 status and systemic inflammation (47). Finally, while inflammation may contribute to lower vitamin B6 status, current evidence fails to support a role for vitamin B6 in the control of inflammation in patients with cardiovascular disease (48, 49).

Cognitive decline and Alzheimer's disease

A few observational studies have linked cognitive decline and Alzheimer's disease (AD) in the elderly with inadequate status of folate, vitamin B12, and vitamin B6(50). Yet, the relationship between B vitamins and cognitive health in aging is complicated by both the high prevalence of hyperhomocysteinemia and signs of systemic inflammation in elderly people (51). On the one hand, since inflammation may impair vitamin B6 metabolism, low serum PLP levels may well be caused by processes related to aging rather than by malnutrition. On the other hand, high serum homocysteine may possibly be a risk factor for cognitive decline in the elderly, although the matter remains under debate. Specifically, the meta-analysis of 19 randomized, placebo-controlled trials of B-vitamin supplementation failed to report any difference in several measures of cognitive function between treatment and placebo groups, despite the treatment effectively lowering homocysteine levels (52). In a recent randomized, double-blind, placebo-controlled study of 2,695 stroke survivors with or without cognitive impairments, daily supplementation with 2 mg of folic acid, 0.5 mg of vitamin B12, and 25 mg of vitamin B6 for 3.4 years resulted in significant reductions in mean homocysteine levels (by 28% and 43% in cognitively unimpaired and impaired patients, respectively) compared to placebo. Yet, the B-vitamin intervention had no effect on either the incidence of newly diagnosed cognitive impairments or on measures of cognitive performance when compared to placebo (53). In contrast, another recent placebo-controlled trial found that a daily B-vitamin regimen that led to significant homocysteine lowering in high-risk elderly individuals could limit the progressive atrophy of gray matter brain regions associated with the AD process (54). Yet, the authors attributed the changes in homocysteine levels primarily to vitamin B12. Because of mixed findings, it is presently unclear whether supplementation with B vitamins might blunt cognitive decline in the elderly. Evidence is needed to determine whether marginal B-vitamin deficiencies, which are relatively common in the elderly, even contribute to age-associated declines in cognitive function, or whether both result from processes associated with aging and/or disease.

Depression

Late-life depression is a common disorder sometimes occurring after acute illnesses, such as hip fracture or stroke(55, 56). Coexistence of symptoms of depression and low vitamin B6 status (plasma PLP level ≤20 nanomoles/liter) has been reported in a few cross-sectional studies(57, 58). In a prospective study of 3,503 free-living people aged 65 and older from the Chicago Health and Aging Project, total vitamin B6 intakes (but not dietary intakes alone) were inversely correlated with the incidence of depressive symptoms during a mean follow-up period of 7.2 years (59). In a randomized, double-blind, placebo-controlled trial in 563 individuals who suffered from a recent stroke, daily supplementation of 2 mg of folic acid, 0.5 mg of vitamin B12, and 25 mg of vitamin B6 halved the risk of developing a major depressive episode during a mean follow-up period of 7.1 years (60). This reduction in risk was associated with a 25% lower level of plasma homocysteine in supplemented patients compared to controls. Additional evidence is needed to evaluate whether B vitamins could be included in the routine management of older people at high risk for depression.

Cancer

Chronic inflammation that underlies most cancers may enhance vitamin B6 degradation (See Vitamin B6 and inflammation above). In addition, the requirement of PLP in the methionine cycle, homocysteinecatabolism, and thymidylate synthesis suggests that low vitamin B6 status may contribute to the onset and/or progression of tumors. The systematic review of nine prospective studies found either inverse or positive associations between vitamin B6 intakes and colorectal cancer (CRC) risk (61). Inconsistent evidence regarding the link between vitamin B6 intakes and breast cancer was also recently reported in a meta-analysis(62). Yet, a prospective study that followed nearly 500,000 older adults for nine years observed that the risk of esophageal and stomach cancers was lower in participants in the highest vs. lowest quintile of total vitamin B6 intakes (median values, 2.7 mg/day vs. 1.4 mg/day) (63). Additionally, a meta-analysis of four nested case-control studies reported a 48% reduction in CRC risk in the highest vs. lowest quartile of blood PLP level (61). Another meta-analysis of five nested case-control studies found higher vs. lower serum PLP levels to be associated with a 29% lower risk of breast cancer in postmenopausal, but not premenopausal, women (62).

Very few randomized, placebo-controlled trials investigating the nature of the association between B vitamins and cancer risk have focused on vitamin B6. Two earlier studies conducted in subjects with coronary artery disease failed to observe any benefit of supplemental vitamin B6 (40 mg/day) on CRC risk and mortality (reviewed in 64). A recent randomized, double-blind, placebo-controlled study conducted in 1,470 women with high cardiovascular risk showed that daily supplementation with 2.5 mg of folic acid, 1 mg of vitamin B12, and 50 mg of vitamin B6 for a mean treatment period of 7.3 years had no effect on the risk of developing colorectal adenoma when compared to placebo (65).

Kidney stones

A large prospective study examined the relationship between vitamin B6 intake and the occurrence of symptomatic kidney stones in women. A group of more than 85,000 women without a prior history of kidney stones were followed over 14 years, and those who consumed 40 mg or more of vitamin B6 daily had only two-thirds the risk of developing kidney stones compared with those who consumed 3 mg or less (66). However, in a group of more than 45,000 men followed for 14 years, no association was found between vitamin B6 intake and the occurrence of kidney stones (67). Limited experimental data have suggested that supplementation with high doses of pyridoxamine may help decrease the formation of calcium oxalate kidney stones and reduce urinary oxalate levels, an important determinant of calcium oxalate kidney stone formation (68, 69). Presently, the relationship between vitamin B6 intake and the risk of developing kidney stones requires further study before any recommendations can be made.

Disease Treatment

Vitamin B6supplements at pharmacologic doses (i.e., doses much larger than those needed to prevent deficiency) have been used in an attempt to treat a wide variety of conditions, some of which are discussed below.

Metabolic diseases

A few rare inborn metabolic disorders, including pyridoxine-dependent epilepsy (PDE) and pyridox(am)ine phosphate oxidase (PNPO) deficiency, are the cause of early-onset epileptic encephalopathies that are found to be responsive to pharmacologic doses of vitamin B6. In individuals affected by PDE and PNPO deficiency, PLP bioavailability is limited, and treatment with pyridoxine and/or PLP have been used to alleviate or abolish epileptic seizures characterizing these conditions (70, 71). Pyridoxine therapy, along with dietary protein restriction, is also used in the management of vitamin B6 responsive homocystinuria caused by the deficiency of the PLP-dependent enzyme, cystathionine beta synthase (72).

Morning sickness

Nausea and vomiting in pregnancy (NVP), often referred to as morning sickness, can affect up to 85% of women during early pregnancy and usually lasts between 12 and 16 weeks (73). Vitamin B6 has been used since the 1940s to treat nausea during pregnancy. Vitamin B6 was originally included in the medication Bendectin, which was prescribed for NVP treatment and later withdrawn from the market due to unproven concerns that it increased the risk for birth defects. Vitamin B6 itself is considered safe during pregnancy and has been used in pregnant women without any evidence of fetal harm (74). The results of two double-blind, placebo-controlled trials, including 401 pregnant women that used 25 mg of pyridoxine every eight hours for three days (75) or 10 mg of pyridoxine every eight hours for five days (76), suggested that vitamin B6 may be beneficial in reducing nausea. A recent systematic review of randomized controlled trials on NVP symptoms during early pregnancy found supplemental vitamin B6 to be somewhat effective (77). It should be noted that NVP usually resolves without any treatment, making it difficult to perform well-controlled trials. More recently, NVP symptoms were evaluated using Pregnancy Unique Quantification of Emesis (PUQE) scores in a randomized, double-blind, placebo-controlled study conducted in 256 pregnant women (7-14 weeks' gestation) suffering from NVP (78). Supplementation with pyridoxine and the drug doxylamine significantly improved NVP symptoms, as assessed by lower PUQE scores compared to placebo. Moreover, more women supplemented with pyridoxine-doxylamine (48.9%) than placebo-treated (32.8%) asked to continue their treatment at the end of the 15-day trial. The American and Canadian Colleges of Obstetrics and Gynecology have recommended the use of vitamin B6 (pyridoxine hydrochloride, 10 mg) and doxylamine succinate (10 mg) as first-line therapy for NVP (73).

Premenstrual syndrome

Premenstrual syndrome (PMS) refers to a cluster of symptoms, including but not limited to fatigue, irritability, moodiness/depression, fluid retention, and breast tenderness, that begin sometime after ovulation (mid-cycle) and subside with the onset of menstruation (the monthly period). A systematic review and meta-analysis of nine randomized, placebo-controlled trials suggested that supplemental vitamin B6, up to 100 mg/day, may be of value to treat PMS, including mood symptoms; however, only limited conclusions could be drawn because most of the studies were of poor quality (79). Another more recent review of 13 randomized controlled studies also emphasized the need for conclusive evidence before recommendations can be made (80).

Depression

The importance of PLP-dependent enzymes in the synthesis of several neurotransmitters (see Nervous system function) has led researchers to consider whether vitamin B6 deficiency may contribute to the onset of depressive symptoms (see Disease Prevention). There is limited evidence suggesting that supplemental vitamin B6 may have therapeutic efficacy in the management of depression. In a randomized, placebo-controlled trial conducted in 225 elderly patients hospitalized for acute illness, a six-month intervention with daily multivitamin/mineral supplements improved nutritional B-vitamin status and decreased the number and severity of depressive symptoms when compared to placebo (81). In addition, while supplement intake effectively reduced plasmahomocysteine levels compared to placebo, the effect of supplementation on depressive symptoms at the end of the trial was greater in treated subjects in the lowest vs. highest quartile of homocysteine levels (≤10 micromoles/liter vs. ≥16.1 micromoles/liter) (82). Yet, the etiology of late-onset depression is unclear and evidence is currently lacking to suggest whether supplemental B vitamins (including vitamin B6) could relieve depressive symptoms.

Carpal tunnel syndrome

Carpal tunnel syndrome (CTS) causes numbness, pain, and weakness of the hand and fingers due to compression of the median nerve at the wrist. It may result from repetitive stress injury of the wrist or from soft-tissue swelling, which sometimes occurs with pregnancy or hypothyroidism. Early studies by the same investigator suggested that supplementation with 100-200 mg/day of vitamin B6 for several months might improve CTS symptoms in individuals with low vitamin B6 status (83, 84). In addition, a cross-sectional study in 137 men not taking vitaminsupplements found that decreased blood levels of PLP were associated with increased pain, tingling, and nocturnal wakening—all symptoms of CTS (85). However, studies using electrophysiological measurements of median nerve conduction have largely failed to find an association between vitamin B6 deficiency and CTS (86). While a few studies have noted some symptomatic relief with vitamin B6 supplementation, double-blind, placebo-controlled trials have not generally found vitamin B6 to be effective in treating CTS (86). Yet, despite its equivocal effectiveness, vitamin B6 supplementation is sometimes used in complementary therapy in an attempt to avoid hand surgery. Patients taking high doses of vitamin B6 should be advised by a physician and monitored for vitamin B6-related toxicity symptoms (see Toxicity) (87).

Sources

Food sources

The analysis of data collected in the US NHANES 2003-2004 has indicated that vitamin B6 intakes from food only averaged about 1.9 mg/day (88). Yet, despite values well above the current RDA, total vitamin B6 intakes (combining food and supplements) below 2 mg/day appear to be associated with relatively high proportions of low vitamin B6 status in all age groups (see Supplements). Many plant foods contain a unique form of vitamin B6 called pyridoxine glucoside; this form of vitamin B6 appears to be only about half as bioavailable as vitamin B6 from other food sources or supplements (7). Vitamin B6 in a mixed diet has been found to be approximately 75% bioavailable (14). In most cases, including foods in the diet that are rich in vitamin B6 should supply enough to meet the current RDA. However, those who follow a very restricted vegetarian diet might need to increase their vitamin B6 intake by eating foods fortified with vitamin B6 or by taking a supplement. Some foods that are relatively rich in vitamin B6 and their vitamin B6 content in milligrams (mg) are listed in the table below. For more information on the nutrient content of specific foods, search the
USDA food composition database.

Food

Serving

Vitamin B6 (mg)

Fortified breakfast cereal

1 cup

0.5-2.5

Salmon, wild (cooked)

3 ounces*

0.48-0.80

Potato, Russet, with skin (baked)

1 medium

0.70

Turkey, light meat (cooked)

3 ounces

0.69

Avocado

1 medium

0.52

Chicken, light meat without skin (cooked)

3 ounces

0.51

Spinach (cooked)

1 cup

0.44

Banana

1 medium

0.43

Dried plums, pitted

1 cup

0.36

Banana

1 medium

0.43

Hazelnuts (dry roasted)

1 ounce

0.18

Vegetable juice cocktail

6 ounces

0.13

*A 3-ounce serving of meat or fish is about the size of
a deck of cards.

Supplements

Vitamin B6 is available as pyridoxine hydrochloride in multivitamin, vitamin B-complex, and vitamin B6supplements(89). In NHANES 2003-2004, low vitamin B6 status (plasma PLP level <20 nanomoles/liter) was reported in 24% of non users of supplements and 11% of supplement users. Moreover, total vitamin B6 intakes (from food and supplements) lower than 2 mg/day were associated with high proportions of low plasma PLP levels: 16% in men aged 13-54 years, 24% in menstruating women, and 26% in individuals aged 65 years and older. Finally, the prevalence of low PLP levels was found to be greater in individuals consuming less than 2 mg/day of vitamin B6 compared to higher intakes. For example, only 14% of men and women aged 65 and older had low PLP values with total vitamin B6 intakes of 2-2.9 mg/day compared to 26% in those consuming less than 2 mg/day of vitamin B6(88).

Safety

Toxicity

Because adverse effects have only been documented from vitamin B6supplements and never from food sources, safety concerning only the supplemental form of vitamin B6 (pyridoxine) is discussed. Although vitamin B6 is a water-soluble vitamin and is excreted in the urine, long-term supplementation with very high doses of pyridoxine may result in painful neurological symptoms known as sensory neuropathy. Symptoms include pain and numbness of the extremities and in severe cases, difficulty walking. Sensory neuropathy typically develops at doses of pyridoxine in excess of 1,000 mg per day. However, there have been a few case reports of individuals who developed sensory neuropathies at doses of less than 500 mg daily over a period of months. Yet, none of the studies in which an objective neurological examination was performed reported evidence of sensory nerve damage at intakes below 200 mg pyridoxine daily (90). To prevent sensory neuropathy in virtually all individuals, the Food and Nutrition Board of the Institute of Medicine set the tolerable upper intake level (UL) for pyridoxine at 100 mg/day for adults (see table below) (14). Because placebo-controlled studies have generally failed to show therapeutic benefits of high doses of pyridoxine, there is little reason to exceed the UL of 100 mg/day.

Tolerable Upper
Intake Level (UL) for Vitamin B6

Age Group

UL (mg/day)

Infants 0-12 months

Not possible to establish*

Children 1-3 years

30

Children 4-8 years

40

Children 9-13 years

60

Adolescents 14-18 years

80

Adults 19 years and older

100

*Source of intake should be from food and formula only.

Drug interactions

Certain medications interfere with the metabolism of vitamin B6; therefore, some individuals may be vulnerable to a vitamin B6 deficiency if supplemental vitamin B6 is not taken. In the NHANES 2003-2004 analysis, significantly more current and past users of oral contraceptives (OCs) among menstruating women had low plasma PLP levels compared to women who have never used OCs, suggesting that the estrogen content of OCs may interfere with vitamin B6 metabolism (see Side effects of oral contraceptives below) (88). Anti-tuberculosis medications (e.g., isoniazid and cycloserine), the metal chelator penicillamine, and anti-parkinsonian drugs like L-Dopa can all form complexes with vitamin B6 and limit its bioavailability, thus creating a functional deficiency. PLP bioavailability may also be reduced by methylxanthines, such as theophylline used to treat certain respiratory conditions (7). The long-term use of nonsteroidal anti-inflammatory drugs (NSAIDs; e.g. celecoxib and naproxen) may also impair vitamin B6 metabolism (91). Conversely, high doses of vitamin B6 have been found to decrease the efficacy of two anticonvulsants, phenobarbital and phenytoin, and of L-Dopa. (6, 90).

Side effects of oral contraceptives

Because vitamin B6 is required for the metabolism of the amino acid tryptophan, the tryptophan load test (an assay of tryptophan metabolites after an oral dose of tryptophan) has been used as a functional assessment of vitamin B6 status. Abnormal tryptophan load tests in women taking high-dose oral contraceptives (OCs) in the 1960s and 1970s suggested that these women were vitamin B6 deficient, which led to the prescription of high doses of vitamin B6 (100-150 mg/day) to women taking OCs. However, most other indices of vitamin B6 status were normal in women on high-dose OCs, and the estrogen content of OCs appeared to be more likely responsible for the abnormality in tryptophan metabolism (88). Yet, more recently, the use of lower dose formulations has also been associated with vitamin B6 inadequacy (88, 92). Although it is not known whether OCs actually impair vitamin B6 metabolism or merely affect the tissue distribution of PLP, the use of OCs may place women at higher risk of vitamin B6 deficiency when they discontinue OCs and become pregnant (93). Whether OC users are at higher risk of cardiovascular disease despite normal homocysteine levels also needs to be determined. Finally, although high doses of vitamin B6 (pyridoxine) have demonstrated no benefit in preventing the risk of side effects from OCs (94), the use of vitamin B6 supplements may be warranted in current and past OC users.

Linus Pauling Institute
Recommendation

The Linus Pauling Institute supports the RDA for vitamin B6. LPI recommends that all adults take a daily multivitamin/mineral supplement, which usually contains at least 2 mg of vitamin B6. This amount is slightly above the RDA but still 50 times lower than the tolerable upper intake level (UL) set by the Food and Nutrition Board (see Safety).

Older adults (> 50 years)

Early metabolic studies have indicated that the requirement for vitamin B6 in older adults is approximately 2 mg daily (95). Yet, the analysis of the US population survey (NHANES) 2003-2004 showed that adequate vitamin B6 status and low homocysteine levels were associated with total vitamin B6 intakes equal to and above 3 mg/day in people aged 65 years and older (88). The Linus Pauling Institute recommends that older adults take a multivitamin/mineral supplement, which provides at least 2.0 mg of vitamin B6 daily.

The 2014 update of this article was underwritten, in part, by a grant from
Bayer Consumer Care AG, Basel, Switzerland.

Copyright 2000-2015 Linus Pauling Institute

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